Determinants of Fe²⁺ over M²⁺ (M = Mg, Mn, Zn) Selectivity in Non-Heme Iron Proteins

Iron cations are indispensable players in a number of vital biological processes such as respiration, cell division, nitrogen fixation, oxygen transport, nucleotide synthesis, oxidant protection, O₂ activation in the metabolism of various organic substrates, gene regulation, and protein structure stabilization. The basic mechanisms and factors governing the competition between Fe²⁺ and other metal species from the cellular fluids such as Mg²⁺, Mn²⁺, and Zn²⁺ are, however, not well understood, and several outstanding questions remain. (i) How does the Fe²⁺ binding site select the "right" cation and protect itself from attacks by other biogenic cations present in the surrounding milieu? (ii) Do the iron binding sites employ different selectivity strategies toward metal cations possessing different ligand affinities and cytosolic concentrations? (iii) What are the key determinants of metal selectivity in Fe²⁺ proteins? In this study, by employing density functional theory calculations combined with polarizable continuum model computations, we endeavor to address these questions by evaluating the thermodynamic outcome of the competition between Fe²⁺ and Mg²⁺/Mn²⁺/Zn²⁺ in model non-heme mononuclear metal binding sites of various compositions and charge states. The present calculations, which are in line with available experimental data, shed light on the mechanism of Fe²⁺-Mg²⁺/Mn²⁺/Zn²⁺ competition in non-heme iron proteins and disclose the key factors governing the process.